The objective of this research proposal is to develop new asymmetric catalytic protocols for hydro- and di-functionalization of unactivated alkenes. Alkenes are some of the most simple chemical building blocks that can be readily elaborated to give products of high value. From our longstanding interest in reversing the typical reactivity patterns of alkenes, we have developed a catalyst system that affords the opposite, or anti-Markovnikov, regioisomers of alkene hydrofunctionalization products.
In Specific Aim 1, we will develop a new catalyst system to accomplish these reactions with control of absolute stereochemistry.
In Specific Aim 2, we will develop new difunctionalization reactions of alkenes based on this general catalyst system that provides the opposite regioselectivity for what is typically observed in previously established methods. In this aim we will also delineate conditions to accomplish these reactions with stereochemical control. We predict that this research program will enhance the synthetic capabilities of medicinal chemists to explore greater chemical space in the development of small molecule therapeutics.

Public Health Relevance

The objective of this research program is to invent new catalytic synthetic protocols for high value transformations of alkenes. Using organic dyes that are designed to transform visible light energy and to chemical energy, new chemical reactions will be developed that have relevance to medicinal compounds.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM098340-07
Application #
9717266
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Yang, Jiong
Project Start
2011-09-01
Project End
2020-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Morse, Peter D; Nguyen, Tien M; Cruz, Cole L et al. (2018) Enantioselective counter-anions in photoredox catalysis: the asymmetric cation radical Diels-Alder reaction. Tetrahedron 74:3266-3272
Griffin, Jeremy D; Cavanaugh, Cortney L; Nicewicz, David A (2017) Reversing the Regioselectivity of Halofunctionalization Reactions through Cooperative Photoredox and Copper Catalysis. Angew Chem Int Ed Engl 56:2097-2100
Margrey, Kaila A; Nicewicz, David A (2016) A General Approach to Catalytic Alkene Anti-Markovnikov Hydrofunctionalization Reactions via Acridinium Photoredox Catalysis. Acc Chem Res 49:1997-2006
Morse, Peter D; Nicewicz, David A (2015) Divergent Regioselectivity in Photoredox-Catalyzed Hydrofunctionalization Reactions of Unsaturated Amides and Thioamides. Chem Sci 6:270-274
Griffin, Jeremy D; Zeller, Mary A; Nicewicz, David A (2015) Hydrodecarboxylation of Carboxylic and Malonic Acid Derivatives via Organic Photoredox Catalysis: Substrate Scope and Mechanistic Insight. J Am Chem Soc 137:11340-8
Romero, Nathan A; Nicewicz, David A (2014) Mechanistic insight into the photoredox catalysis of anti-markovnikov alkene hydrofunctionalization reactions. J Am Chem Soc 136:17024-35
Nicewicz, David A; Hamilton, David S (2014) Organic Photoredox Catalysis as a General Strategy for Anti-Markovnikov Alkene Hydrofunctionalization. Synlett 25:1191-1196
Zeller, Mary A; Riener, Michelle; Nicewicz, David A (2014) Butyrolactone synthesis via polar radical crossover cycloaddition reactions: diastereoselective syntheses of methylenolactocin and protolichesterinic acid. Org Lett 16:4810-3
Nguyen, Tien M; Manohar, Namita; Nicewicz, David A (2014) anti-Markovnikov hydroamination of alkenes catalyzed by a two-component organic photoredox system: direct access to phenethylamine derivatives. Angew Chem Int Ed Engl 53:6198-201
Perkowski, Andrew J; Nicewicz, David A (2013) Direct catalytic anti-Markovnikov addition of carboxylic acids to alkenes. J Am Chem Soc 135:10334-7

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